Integrating wearables and modelling for monitoring rehabilitation following total knee joint replacement.

BACKGROUND AND OBJECTIVE: Wearable inertial devices integrated with modelling and cloud computing have been widely adopted in the sports sector, however, their use in the health and medical field has yet to be fully realised. To date, there have been no reported studies concerning the use of wearables as a surrogate tool to monitor knee joint loading during recovery following a total knee joint replacement. The objective of this study is to firstly evaluate if peak tibial acceleration from wearables during gait is a good surrogate metric for computer modelling predicted functional knee loading; and secondly evaluate if traditional clinical patient related outcomes measures are consistent with wearable predictions. METHODS: Following ethical approval, four healthy participants were used to establish the relationship between computer modelling predicted knee joint loading and wearable measured tibial acceleration. Following this, ten patients who had total knee joint replacements were then followed during their 6-week rehabilitation. Gait analysis, wearable acceleration, computer models of knee joint loading, and patient related outcomes measures including the Oxford knee score and range of motion were recorded. RESULTS: A linear correlation (R2 of 0.7-0.97) was observed between peak tibial acceleration (from wearables) and musculoskeletal model predicted knee joint loading during gait in healthy participants first. Whilst patient related outcome measures (Oxford knee score and patient range of motion) were observed to improve consistently during rehabilitation, this was not consistent with all patient's tibial acceleration. Only those patients that exhibited increasing peak tibial acceleration over 6-weeks rehabilitation were positively correlated with the Oxford knee score (R2 of 0.51 to 0.97). Wearable predicted tibial acceleration revealed three patients with a consistent knee loading, five patients with improving knee loading, and two patients with declining knee loading during recovery. Hence, 20% of patients did not present with satisfactory joint loading following total knee joint replacement and this was not detected with current patient related outcome measures. CONCLUSIONS: The use of inertial measurement units or wearables in this study provided additional insight into patients who were not exhibiting functional improvements in joint loading, and offers clinicians an 'off-site' early warning metric to identify potential complications during recovery and provide the opportunity for early intervention. This study has important implications for improving patient outcomes, equity, and for those who live in rural regions.

Automated creation and tuning of personalised muscle paths for OpenSim musculoskeletal models of the knee joint.

Computational modelling is an invaluable tool for investigating features of human locomotion and motor control which cannot be measured except through invasive techniques. Recent research has focussed on creating personalised musculoskeletal models using population-based morphing or directly from medical imaging. Although progress has been made, robust definition of two critical model parameters remains challenging: (1) complete tibiofemoral (TF) and patellofemoral (PF) joint motions, and (2) muscle tendon unit (MTU) pathways and kinematics (i.e. lengths and moment arms). The aim of this study was to develop an automated framework, using population-based morphing approaches to create personalised musculoskeletal models, consisting of personalised bone geometries, TF and PF joint mechanisms, and MTU pathways and kinematics. Informed from medical imaging, personalised rigid body TF and PF joint mechanisms were created. Using atlas- and optimisation-based methods, personalised MTU pathways and kinematics were created with the aim of preventing MTU penetration into bones and achieving smooth MTU kinematics that follow patterns from existing literature. This framework was integrated into the Musculoskeletal Atlas Project Client software package to create and optimise models for 6 participants with incrementally increasing levels of personalisation with the aim of improving MTU kinematics and pathways. Three comparisons were made: (1) non-optimised (Model 1) and optimised models (Model 3) with generic joint mechanisms; (2) non-optimised (Model 2) and optimised models (Model 4) with personalised joint mechanisms; and (3) both optimised models (Model 3 and 4). Following optimisation, improvements were consistently shown in pattern similarity to cadaveric data in comparison (1) and (2). For comparison (3), a number of comparisons showed no significant difference between the two compared models. Importantly, optimisation did not produce statistically significantly worse results in any case.

Effect of fructose on markers of non-alcoholic fatty liver disease (NAFLD): a systematic review and meta-analysis of controlled feeding trials.

BACKGROUND/OBJECTIVES: In the absence of consistent clinical evidence, there are concerns that fructose contributes to non-alcoholic fatty liver disease (NAFLD). To determine the effect of fructose on markers of NAFLD, we conducted a systematic review and meta-analysis of controlled feeding trials. SUBJECTS/METHODS: We searched MEDLINE, EMBASE, CINAHL and the Cochrane Library (through 3 September 2013). We included relevant trials that involved a follow-up of ≥ 7 days. Two reviewers independently extracted relevant data. Data were pooled by the generic inverse variance method using random effects models and expressed as standardized mean difference (SMD) for intrahepatocellular lipids (IHCL) and mean difference (MD) for alanine aminotransferase (ALT). Inter-study heterogeneity was assessed (Cochran Q statistic) and quantified (I(2) statistic). RESULTS: Eligibility criteria were met by eight reports containing 13 trials in 260 healthy participants: seven isocaloric trials, in which fructose was exchanged isocalorically for other carbohydrates, and six hypercaloric trials, in which the diet was supplemented with excess energy (+21-35% energy) from high-dose fructose (+104-220 g/day). Although there was no effect of fructose in isocaloric trials, fructose in hypercaloric trials increased both IHCL (SMD=0.45 (95% confidence interval (CI): 0.18, 0.72)) and ALT (MD=4.94 U/l (95% CI: 0.03, 9.85)). LIMITATIONS: Few trials were available for inclusion, most of which were small, short (≤ 4 weeks), and of poor quality. CONCLUSIONS: Isocaloric exchange of fructose for other carbohydrates does not induce NAFLD changes in healthy participants. Fructose providing excess energy at extreme doses, however, does raise IHCL and ALT, an effect that may be more attributable to excess energy than fructose. Larger, longer and higher-quality trials of the effect of fructose on histopathological NAFLD changes are required.

Morphogenetic action through flux-limited spreading.

A central question in biology is how secreted morphogens act to induce different cellular responses within a group of cells in a concentration-dependent manner. Modeling morphogenetic output in multicellular systems has so far employed linear diffusion, which is the normal type of diffusion associated with Brownian processes. However, there is evidence that at least some morphogens, such as Hedgehog (Hh) molecules, may not freely diffuse. Moreover, the mathematical analysis of such models necessarily implies unrealistic instantaneous spreading of morphogen molecules, which are derived from the assumptions of Brownian motion in its continuous formulation. A strict mathematical model considering Fick's diffusion law predicts morphogen exposure of the whole tissue at the same time. Such a strict model thus does not describe true biological patterns, even if similar and attractive patterns appear as results of applying such simple model. To eliminate non-biological behaviors from diffusion models we introduce flux-limited spreading (FLS), which implies a restricted velocity for morphogen propagation and a nonlinear mechanism of transport. Using FLS and focusing on intercellular Hh-Gli signaling, we model a morphogen gradient and highlight the propagation velocity of morphogen particles as a new key biological parameter. This model is then applied to the formation and action of the Sonic Hh (Shh) gradient in the vertebrate embryonic neural tube using our experimental data on Hh spreading in heterologous systems together with published data. Unlike linear diffusion models, FLS modeling predicts concentration fronts and the evolution of gradient dynamics and responses over time. In addition to spreading restrictions by extracellular binding partners, we suggest that the constraints imposed by direct bridges of information transfer such as nanotubes or cytonemes underlie FLS. Indeed, we detect and measure morphogen particle velocity in such cell extensions in different systems.

Effect of non-oil-seed pulses on glycaemic control: a systematic review and meta-analysis of randomised controlled experimental trials in people with and without diabetes.

AIMS/HYPOTHESIS: Dietary non-oil-seed pulses (chickpeas, beans, peas, lentils, etc.) are a good source of slowly digestible carbohydrate, fibre and vegetable protein and a valuable means of lowering the glycaemic-index (GI) of the diet. To assess the evidence that dietary pulses may benefit glycaemic control, we conducted a systematic review and meta-analysis of randomised controlled experimental trials investigating the effect of pulses, alone or as part of low-GI or high-fibre diets, on markers of glycaemic control in people with and without diabetes. METHODS: We searched MEDLINE, EMBASE, CINAHL, and the Cochrane Library for relevant controlled trials of >or=7 days. Two independent reviewers (A. Esfahani and J. M. W. Wong) extracted information on study design, participants, treatments and outcomes. Data were pooled using the generic inverse variance method and expressed as standardised mean differences (SMD) with 95% CIs. Heterogeneity was assessed by chi (2) and quantified by I (2). Meta-regression models identified independent predictors of effects. RESULTS: A total of 41 trials (39 reports) were included. Pulses alone (11 trials) lowered fasting blood glucose (FBG) (-0.82, 95% CI -1.36 to -0.27) and insulin (-0.49, 95% CI -0.93 to -0.04). Pulses in low-GI diets (19 trials) lowered glycosylated blood proteins (GP), measured as HbA(1c) or fructosamine (-0.28, 95% CI -0.42 to -0.14). Finally, pulses in high-fibre diets (11 trials) lowered FBG (-0.32, 95% CI -0.49 to -0.15) and GP (-0.27, 95% CI -0.45 to -0.09). Inter-study heterogeneity was high and unexplained for most outcomes, with benefits modified or predicted by diabetes status, pulse type, dose, physical form, duration of follow-up, study quality, macronutrient profile of background diets, feeding control and design. CONCLUSIONS/INTERPRETATION: Pooled analyses demonstrated that pulses, alone or in low-GI or high-fibre diets, improve markers of longer term glycaemic control in humans, with the extent of the improvements subject to significant inter-study heterogeneity. There is a need for further large, well-designed trials.

Couples' reports of support for smoking cessation predicting women's late pregnancy cessation.

PURPOSE: Although social support has been linked to smoking cessation, no studies have examined whether social support predicts women's late pregnancy cessation. Further, few have included reports from both support recipients and providers. DESIGN: Longitudinal. SUBJECTS: Pregnant couples (n = 394) reported support for cessation in early (13-20 weeks) and late (28 weeks) pregnancy. MEASURES: Different measures of couples' support were tested for predicting women's late pregnancy, cessation. Measures of couples' support that were calculated included: summative (added women's and male partners' support scores, possible range 2-10), difference (subtracted the lower score from the higher, possible range 0-4), strong link (used higher positive or lower negative score, possible range 1-5), weak link (lower positive or higher negative score, possible range 1-5), and female and male reports alone (possible ranges 1-5). Covariate-adjusted odds ratios for the association of these various measures of couples' support with women's late pregnancy cessation were calculated. RESULTS: Of the 12 scores (6 positive, 6 negative), only summative (p = .03) and weak link (p = .05) for positive support predicted women's quitting. CONCLUSION: Neither women's nor male partners' reports alone predicted women's cessation; only when both scores were considered, either by adding the scores or by taking the lower score, was the positive support score predictive. Future studies of social support should include support recipients' and providers' perspectives.

Compact, continuous-wave, singly resonant optical parametric oscillator based on periodically poled RbTiOAsO4 in a Nd:YVO4 laser.

We describe a compact all-solid-state continuous-wave, singly resonant optical parametric oscillator (SRO) based on periodically poled RbTiOAsO4. The SRO is pumped at 1.064 microm by a Nd:YVO4 laser, which is itself pumped by a 3-W diode laser. Using the intracavity technique produced an oscillation threshold for the SRO of only 1.6 W (diode-laser power). For 3 W of diode pump power some 65 mW was obtained in the (nonresonant) idler (wavelength 3.52 microm). Temperature tuning over the range 10-100 degrees C resulted in tuning ranges of 1.52-1.54 and 3.41-3.54 microm for the signal and the idler waves, respectively. Importantly, relaxation oscillations were absent.

Dose-dependent, prion protein (PrP)-mediated facilitation of excitatory synaptic transmission in the mouse hippocampus.

Disruption of both alleles of the prion protein gene, Prnp, has been shown repeatedly to abolish the susceptibility of mice to developing prion diseases. However, conflicting results have been obtained from phenotypic analyses of prion protein (PrP)-deficient (Prnp0/0) mice lines. To explore the possible neurophysiological properties associated with expression or absence of the normal isoform of the cellular prion protein (PrPC), we used conventional in vitro extracellular field potential recordings in the hippocampal CA1 area of mice from two independently-derived Prnp0/0 strains. Basal synaptic transmission and a short-term form of synaptic plasticity were analysed in this study. Results were compared with animals carrying a wild-type mouse PrP transgene to investigate whether PrP expression levels influence glutamatergic synaptic transmission in the hippocampus. There was a clear correlation between excitatory synaptic transmission and PrP expression; i.e. the range of synaptic responses increased with the level of PrPC expression. On the other hand, the probability of transmitter release, as assessed by paired-pulse facilitation, appeared unchanged. Interestingly, whereas the overall range for synaptic responses was still greater in older mice over-expressing PrPC, this effect in these animals appeared to be due to better recruitment of fibres rather than facilitation of synaptic transmission per se. Taken together, these data are strong evidence for a functional role for PrPC in modulating synaptic transmission.

A dendrodendritic reciprocal synapse provides a recurrent excitatory connection in the olfactory bulb.

Neuronal synchronization in the olfactory bulb has been proposed to arise from a diffuse action of glutamate released from mitral cells (MC, olfactory bulb relay neurons). According to this hypothesis, glutamate spills over from dendrodendritic synapses formed between MC and granule cells (GC, olfactory bulb interneurons) to activate neighboring MC. The excitation of MC is balanced by a strong inhibition from GC. Here we show that MC excitation is caused by glutamate released from bulbar interneurons located in the GC layer. These reciprocal synapses depend on an unusual, 2-amino-5-phosphonovaleric acid-resistant, N-methyl-d-aspartate receptor. This type of feedback excitation onto relay neurons may strengthen the original sensory input signal and further extend the function of the dendritic microcircuit within the main olfactory bulb.

Bicoid-independent formation of thoracic segments in Drosophila.

The maternal determinant Bicoid (Bcd) represents the paradigm of a morphogen that provides positional information for pattern formation. However, as bicoid seems to be a recently acquired gene in flies, the question was raised as to how embryonic patterning is achieved in organisms with more ancestral modes of development. Because the phylogenetically conserved Hunchback (Hb) protein had previously been shown to act as a morphogen in abdominal patterning, we asked which functions of Bcd could be performed by Hb. By reestablishing a proposed ancient regulatory circuitry in which maternal Hb controls zygotic hunchback expression, we show that Hb is able to form thoracic segments in the absence of Bcd.

Multiple and opposing roles of cholinergic transmission in the main olfactory bulb.

The main olfactory bulb is a critical relay step between the olfactory epithelium and the olfactory cortex. A marked feature of the bulb is its massive innervation by cholinergic inputs from the basal forebrain. In this study, we addressed the functional interaction between cholinergic inputs and intrinsic bulbar circuitry. Determining the roles of acetylcholine (ACh) requires the characterization of cholinergic effects on both neural excitability and synaptic transmission. For this purpose, we used electrophysiological techniques to localize and characterize the diverse roles of ACh in mouse olfactory bulb slices. We found that cholinergic inputs have a surprising number of target receptor populations that are expressed on three different neuronal types in the bulb. Specifically, nicotinic acetylcholine receptors excite both the output neurons of the bulb, i.e., the mitral cells, as well as interneurons located in the periglomerular regions. These nicotine-induced responses in interneurons are short lasting, whereas responses in mitral cells are long lasting. In contrast, muscarinic receptors have an inhibitory effect on the firing rate of interneurons from a deeper layer, granule cells, while at the same time they increase the degree of activity-independent transmitter release from these cells onto mitral cells. Cholinergic signaling thus was found to have multiple and opposing roles in the olfactory bulb. These dual cholinergic effects on mitral cells and interneurons may be important in modulating olfactory bulb output to central structures required for driven behaviors and may be relevant to understanding mechanisms underlying the perturbations of cholinergic inputs to cortex that occur in Alzheimer's disease.

Long-term but not short-term plasticity at mossy fiber synapses is impaired in neural cell adhesion molecule-deficient mice.

Cell adhesion molecules (CAMs) are known to be involved in a variety of developmental processes that play key roles in the establishment of synaptic connectivity during embryonic development, but recent evidence implicates the same molecules in synaptic plasticity of the adult. In the present study, we have used neural CAM (NCAM)-deficient mice, which have learning and behavioral deficits, to evaluate NCAM function in the hippocampal mossy fiber system. Morphological studies demonstrated that fasciculation and laminar growth of mossy fibers were strongly affected, leading to innervation of CA3 pyramidal cells at ectopic sites, whereas individual mossy fiber boutons appeared normal. Electrophysiological recordings performed in hippocampal slice preparations revealed that both basal synaptic transmission and two forms of short-term plasticity, i.e., paired-pulse facilitation and frequency facilitation, were normal in mice lacking all forms of NCAM. However, long-term potentiation of glutamatergic excitatory synapses after brief trains of repetitive stimulation was abolished. Taken together, these results strongly suggest that in the hippocampal mossy fiber system, NCAM is essential both for correct axonal growth and synaptogenesis and for long-term changes in synaptic strength.

Multiple osteosclerotic masses of the jaw.

Florid osseous dysplasia is a peculiar reactive or developmental bone disease that is known to appear only in the jaws. It has an inexplicable decided predilection for occurrence in middle-aged, black women. Extent of the disease may vary from a few isolated periapical lesions to diffuse involvement of the mandibular and maxillary alveolar processes. Radiographically, it is characterized by multiquadrant, globular, radiolucent-radiopaque lesions. Histopathologically, it is a benign fibro-osseous lesion that must be differentiated from other benign fibro-osseous lesions such as fibrous dysplasia, ossifying fibroma, Paget's disease, and sclerosing osteomyelitis on the basis of combined clinical, radiographic, and histological features. Correctly identifying this disease is important because it requires no treatment unless a secondary osteomyelitis develops. Sequestrae and osteomyelitis are complications arising when teeth are removed and removable dental prostheses are supported by diseased bone.